What are the next steps for a 37-year-old patient with normocytic anemia (hemoglobin of 116 g/L), normal ferritin levels, and normal Mean Corpuscular Volume (MCV), for further investigations and management?

Normocytic Anemia with Normal Ferritin: Further Investigations

In a 37-year-old woman with normocytic anemia (hemoglobin 116 g/L), normal MCV, and normal ferritin, the next essential steps are to obtain a reticulocyte count, peripheral blood smear, and assess for chronic disease or inflammation with inflammatory markers (CRP, ESR). 1, 2

Initial Diagnostic Workup

Essential Laboratory Tests

• Reticulocyte count (corrected reticulocyte index): This distinguishes between hypoproliferative anemia (low reticulocyte count) and hemolytic/blood loss anemia (elevated reticulocyte count). 1, 2

• Peripheral blood smear: Critical for identifying red cell morphology abnormalities, schistocytes (suggesting hemolysis or thrombotic microangiopathy), or other diagnostic clues. 1, 2

• Red cell distribution width (RDW): An elevated RDW may indicate combined deficiencies (e.g., coexisting iron and folate deficiency) that can mask each other and present with normal MCV. 3, 4

• Inflammatory markers (CRP, ESR): Essential to identify anemia of chronic disease, the most common cause of normocytic anemia. 2, 5

Interpretation Based on Ferritin and Inflammation

While ferritin is normal in this patient, context matters:

• If inflammation is present (elevated CRP/ESR): Ferritin up to 100 μg/L may still indicate iron deficiency, as ferritin is an acute phase reactant. Check transferrin saturation (<20% suggests functional iron deficiency). 3

• If no inflammation: Normal ferritin (>30 μg/L) effectively rules out iron deficiency. 3

Algorithmic Approach Based on Reticulocyte Count

If Reticulocyte Count is LOW or NORMAL (Hypoproliferative)

This suggests impaired red cell production. Proceed with:

• Renal function testing (serum creatinine, calculated GFR): Chronic kidney disease is a common cause of normocytic anemia due to decreased erythropoietin production. 3, 2

• Thyroid function (TSH, free T4 if TSH abnormal): Hypothyroidism commonly causes normocytic anemia. 4

• Vitamin B12 and folate levels: Although typically causing macrocytic anemia, early deficiency or combined deficiencies can present with normal MCV. 4

• Liver function tests: Chronic liver disease can cause anemia of chronic disease. 5

• Consider bone marrow examination only if the above workup is unrevealing and anemia is progressive or severe, though this is rarely contributive in asymptomatic normocytic anemia. 6

If Reticulocyte Count is ELEVATED (Regenerative)

This suggests hemolysis or recent blood loss. Proceed with:

• Hemolysis markers: Lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin, and direct antiglobulin test (DAT/Coombs). 2

• Assess for occult blood loss: Stool occult blood testing, and consider menstrual history in premenopausal women. 3

• If schistocytes present on smear: Urgent evaluation for thrombotic microangiopathy with ADAMTS13 activity level. 7

Common Causes to Consider

Anemia of Chronic Disease/Inflammation

• Most common normocytic anemia, found in 6% of hospitalized patients. 1
• Characterized by elevated inflammatory markers, normal-to-elevated ferritin (>100 μg/L), and transferrin saturation <20%. 3, 5
• Treatment focuses on managing the underlying inflammatory condition. 5

Occult Blood Loss

• Even with normal ferritin, consider gastrointestinal evaluation if there are risk factors (NSAID use, family history of GI malignancy, age >50). 3
• Upper GI endoscopy with small bowel biopsies (to exclude celiac disease, found in 2-3% of iron deficiency cases) and colonoscopy may be warranted. 3

Early or Mixed Deficiency States

• Combined iron and folate/B12 deficiency can neutralize each other's effect on MCV, presenting as normocytic. An elevated RDW is the key clue. 3, 4

Critical Pitfalls to Avoid

• Do not assume dietary insufficiency alone explains anemia without full investigation, especially in women of reproductive age where occult GI pathology must be excluded. 3

• Do not overlook inflammation: Ferritin between 30-100 μg/L in the presence of inflammation may still represent iron deficiency. Check transferrin saturation. 3

• Do not perform bone marrow examination prematurely: It is rarely contributive in asymptomatic normocytic anemia and should be reserved for cases where non-invasive testing is unrevealing. 6

• Do not delay hemolysis workup if reticulocyte count is elevated, as conditions like thrombotic microangiopathy require urgent intervention. 7, 2

When to Refer

• Hematology referral is appropriate if the cause remains unclear after comprehensive evaluation, or if myelodysplastic syndrome is suspected (especially with cytopenias in other cell lines). 4

• Gastroenterology referral for endoscopic evaluation if occult GI blood loss is suspected or if celiac disease screening is positive. 3

• Nephrology referral if chronic kidney disease is identified with abnormal creatinine or GFR. 3